共查询到20条相似文献,搜索用时 46 毫秒
1.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Akifumi Morimoto Ken-ichi Kasahara Shigeki Ohashi Hiroko Suzuki Takahiko Hayashi Shiro Miyoshi 《Bioorganic & medicinal chemistry letters》2013,23(22):6064-6067
We describe a medicinal chemistry approach to generate a series of 2-(1H-pyrazol-1-yl)thiazole compounds that act as selective EP1 receptor antagonists. The obtained results suggest that compound 12 provides the best EP1 receptor antagonist activity and demonstrates good oral pharmacokinetics. 相似文献
2.
Akihiro Kinoshita Masato Higashino Koji Yoshida Yoshiyuki Aratani Akito Kakuuchi Keisuke Hanada Hiroyuki Takeda Atsushi Naganawa Hidekazu Matsuya Kazuyuki Ohmoto 《Bioorganic & medicinal chemistry》2018,26(1):200-214
A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2?=?1.1?nM, EP3?=?1.0?nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01?mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB. 相似文献
3.
Masakazu Atobe Kenji Naganuma Masashi Kawanishi Takahiko Hayashi Hiroko Suzuki Masahiro Nishida Hirokazu Arai 《Bioorganic & medicinal chemistry letters》2018,28(14):2408-2412
We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4?weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing. 相似文献
4.
Li L Mathieu MC Denis D Therien AG Wang Z 《Bioorganic & medicinal chemistry letters》2011,21(2):734-737
We disclose herein our preliminary SAR study on the identification of substituted benzothiophene derivatives as PGE2 subtype 4 receptor antagonists. A potent EP4 antagonist 6a (Ki = 1.4 nM with 10% HSA) was identified. Furthermore, we found that an acidic group was not essential for the EP4 antagonizing activity in the series and neutral replacements were identified. This opens a new direction for future EP4 antagonist design. 相似文献
5.
《Bioorganic & medicinal chemistry letters》2014,24(5):1327-1333
We have designed a series of potent EP1 receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity. In particular, the increase using 22 was approximately 2-fold that of the baseline. More detailed profiling of this compound and further optimization of this series promises to provide a novel class of drug for treating overactive bladder (OAB). 相似文献
6.
《Bioorganic & medicinal chemistry letters》2020,30(10):127104
Novel prostaglandin E2 receptor 4 (EP4) agonists featuring a pyridone core and an allylic alcohol ω-chain were discovered. These agonists were shown to be selective over EP1, EP2 and EP3. Analogs harboring a 4-carboxylic acid phenethyl α-chain displayed improved potency over those containing an n-heptanoic acid chain. Key SAR relationships were also identified. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2019,29(21):126667
Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM – antagonist mode) and D2 (compound 15, Ki = 7 nM – antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors. 相似文献
8.
Morales-Ramos ÁI Li YH Hilfiker M Mecom JS Eidam P Shi D Tseng PS Brooks C Zhang D Wang N Jaworski JP Morrow D Fries H Edwards R Jin J 《Bioorganic & medicinal chemistry letters》2011,21(10):2806-2811
Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP3 receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed. 相似文献
9.
《Bioorganic & medicinal chemistry》2020,28(13):115489
Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia. 相似文献
10.
《Bioorganic & medicinal chemistry》2014,22(5):1782-1790
Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2–4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure–activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability. 相似文献
11.
Jos H.M. Lange Amos Attali Martina A.W. van der Neut Henri C. Wals Arie Mulder Hicham Zilaout Ate Duursma Hans H.M. van Aken Bernard J. van Vliet 《Bioorganic & medicinal chemistry letters》2010,20(17):4992-4998
The synthesis and SAR of 3-alkyl-4-aryl-4,5-dihydropyrazole-1-carboxamides 1–23 and 1-alkyl-5-aryl-4,5-dihydropyrazole-3-carboxamides 24–27 as two novel cannabinoid CB1 receptor agonist classes were described. The target compounds elicited high affinities to the CB1 as well as the CB2 receptor and were found to act as CB1 receptor agonists. The key compound 19 elicited potent CB1 agonistic and CB2 inverse agonistic properties in vitro and showed in vivo activity in a rodent model for multiple sclerosis after oral administration. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(9):2212-2221
In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10 mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. 相似文献
13.
Nian Zhou Alexandre M. Polozov Matthew O’Connell James Burgeson Peng Yu Wayne Zeller Jun Zhang Emmanuel Onua Jose Ramirez Gudrun A. Palsdottir Gudrun V. Halldorsdottir Thorkell Andresson Alex S. Kiselyov Mark Gurney Jasbir Singh 《Bioorganic & medicinal chemistry letters》2010,20(8):2658-2664
A series of novel 1,7-disubstituted oxyindoles were shown to be potent and selective EP3 receptor antagonists. Variation of substitution pattern at the C-3 position of indole enhanced in vitro metabolic stability of the resulting derivatives. Series 27a–c showed >1000-fold selectivity over a panel of prostanoid receptors including IP, FP, EP1, EP2 and EP4. These agents also featured low CYP inhibition and good activity in the functional rat platelet aggregation assay. 相似文献
14.
Adrian Hall Andy Billinton Susan H. Brown Anita Chowdhury Nicholas M. Clayton Gerard M.P. Giblin Mairi Gibson Paul A. Goldsmith David N. Hurst Alan Naylor Caroline F. Peet Tiziana Scoccitti Alexander W. Wilson Wendy Winchester 《Bioorganic & medicinal chemistry letters》2009,19(9):2599-2603
We describe the medicinal chemistry programme that led to the identification of the EP1 receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study. 相似文献
15.
Takuto Kojima Michiyo Mochizuki Takafumi Takai Yasutaka Hoashi Sachie Morimoto Masaki Seto Minoru Nakamura Katsumi Kobayashi Yuu Sako Maiko Tanaka Naoyuki Kanzaki Yohei Kosugi Takahiko Yano Kazuyoshi Aso 《Bioorganic & medicinal chemistry》2018,26(9):2229-2250
A new class of corticotropin releasing factor 1 (CRF1) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a–e were designed as CRF1 receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF1 receptor antagonist. The synthesized tricyclic derivatives 2a–e showed CRF1 receptor binding activity with IC50 values of less than 400?nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF1 receptor binding activity (IC50?=?7.1?nM). To optimize the pharmacokinetic profiles of lead compound 2e, we explored suitable substituents on the 1-position and 6-position, leading to the identification of compound 42c-R, which exhibited potent CRF1 receptor binding activity (IC50?=?58?nM) with good oral bioavailability (F?=?68% in rats). Compound 42c-R exhibited dose-dependent inhibition of [125I]-CRF binding in the frontal cortex (5 and 10?mg/kg, p.o.) as well as suppression of locomotor activation induced by intracerebroventricular administration of CRF in rats (10?mg/kg, p.o.). These results suggest that compound 42c-R successfully binds CRF1 receptors in the brain and exhibits the potential to be further examined for clinical studies. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(8):1934-1940
Synthesis and structure–activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose. 相似文献
17.
《Bioorganic & medicinal chemistry》2016,24(19):4675-4691
A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50 = 27 nM, 56 nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20 mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method. 相似文献
18.
Axel R. Stoit Jos H.M. Lange Hein K.A.C. Coolen Annemieke Rensink Adri van den Hoogenband Arnold P. den Hartog Sjoerd van Schaik Chris G. Kruse 《Bioorganic & medicinal chemistry letters》2018,28(3):459-465
The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6–34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats. 相似文献
19.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan R Craighead M Desai H Ho KK MacSweeney C Milne R Richard Morphy J Neagu I Ohlmeyer MH Pick J Presland J Riviello C Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(12):3813-3817
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献
20.
Napier SE Letourneau JJ Ansari N Auld DS Baker J Best S Campbell-Wan L Chan JH Craighead M Desai H Goan KA Ho KK Hulskotte EG MacSweeney CP Milne R Morphy JR Neagu I Ohlmeyer MH Peeters AW Presland J Riviello C Ruigt GS Thomson FJ Zanetakos HA Zhao J Webb ML 《Bioorganic & medicinal chemistry letters》2011,21(6):1871-1875
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V1b (V3) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V1b receptor and good selectivity with respect to related receptors V1a, V2 and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction. 相似文献